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10.1245/s10434-006-9242-2
Annals of Surgical Oncology 14:1551-1559 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Restaging of Differentiated Thyroid Carcinoma by the Sixth Edition AJCC/UICC TNM Staging System: Stage Migration and Predictability

Brian Lang, MS, FRACS1, Chung-Yau Lo, MS, FRCS (Edin), FACS1, Wai-Fan Chan, MBBS, FRCS1, King-Yin Lam, MD, FRCPA2 and Koon-Yat Wan, MBBS, FRCR3

1 Division of Endocrine Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China
2 Discipline of Pathology, School of Medicine, Griffith University, Gold Coast, Australia
3 Department of Clinical Oncology, University of Hong Kong Medical Centre, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China

Correspondence: Address correspondence and reprint requests to: Chung-Yau Lo, MS, FRCS (Edin), FACS; E-mail: cylo{at}hkucc.hku.hk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Background: The AJCC/UICC TNM staging system (TNM) is a widely accepted system for differentiated thyroid carcinoma (DTC). The objective of the present study was to evaluate the potential changes in cancer-specific survival (CSS) after reclassification from fifth to sixth edition TNM.

Methods: A total of 760 DTC patients managed at our institution from 1961 to 2001 were retrospectively restaged from the fifth to sixth edition TNM. CSS were calculated using Kaplan–Meier method and were compared by the log-rank test. The relative ability of each edition in predicting CSS was calculated by the proportion of variance explained (PVE).

Results: Upon reclassification, the proportion of T1 and T3 tumors increased from 14.2 to 33.4% and 10.0 to 33.7%; T2 and T4 decreased from 44.2 to 25.0% and 31.6 to 7.9%, respectively; N0 remained unchanged at 66.0%; N1a decreased from 25.7 to 4.7%; N1b increased from 8.4 to 29.3%; stages I and IV tumors increased from 55.7 to 60.3% and 3.4 to 17.6%, respectively; stages II and III tumors decreased from 20.5 to 13.9% and 20.4 to 8.2%, respectively. The sixth edition had a higher PVE value than the fifth edition. Significant differences in CSS were observed between stage III (fifth edition) and stage III (sixth edition) and between stage IV (fifth edition) and stage IVA (sixth edition).

Conclusions: The sixth edition TNM caused marked changes in the pT, pN and allocation of patients into different tumor stages. It appeared to have superior predictability over the fifth edition.

Key Words: TNM • Differentiated thyroid carcinoma • Papillary thyroid carcinoma • Follicular thyroid carcinoma • Staging • Risk stratification


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The AJCC/UICC TNM staging system (TNM) has become a widely accepted system for differentiated thyroid carcinoma (DTC) and is currently in its sixth edition.1 Unlike other staging systems for DTC such as the EORTC, AMES, NTCTCS,2–4 the TNM is the only system which undergoes regular revisions in order to keep up with the prevailing view on cancer staging and management.1,5 When compared to its former or the fifth edition, there have been a number of important changes and these include changes in the anatomical extent of the primary tumor (pT), in regional lymph node metastases (pN) as well as in tumor stage grouping (see Table 1Go).6 In brief, under the new pT, T1 tumors have been redefined as those measuring up to 2 cm in maximum diameter instead of the previous 1 cm and T2 tumors as those measuring >2 and ≤4 cm. T3 have been redefined as those measuring >4 cm or with minimal extrathyroidal extension and T4 have been subdivided into T4a, which include those extending beyond thyroid capsule and invasion of either subcutaneous soft tissue, larynx, trachea, esophagus or recurrent laryngeal nerve and T4b, which are those invaded to the prevertebral fascia, mediastinal vessels, or encasing the carotid artery. The pN has also changed with the new N1a implying metastases to level VI lymph nodes and N1b implying metastases to either ipsilateral, contralateral or bilateral cervical lymph node metastases. In tumor stage groupings, although they remain unchanged in those aged <45 years, all stages except stage I have been revised in those aged ≥45 years (see Table 1Go).


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  		TABLE 1. Comparison of the AJCC/UICC fifth and sixth edition TNM staging systems for differentiated thyroid carcinoma
 
Previous studies had focused primarily on the impact of the current pT changes on survival7–9 but had not evaluated the potential changes in predictability and cancer-specific survival (CSS) after reclassification of DTC from fifth to sixth edition TNM. These changes might be important as subsequent surgical and adjuvant treatment primarily depend on the final tumor stage and its predicted CSS (the so-called stage specific treatment).1,10,11

The present study aimed at evaluating these potential changes in CSS when the fifth and sixth editions were applied to the same patient cohort within a single institution according to the instructions of AJCC cancer staging manual.12–14


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
From 1961 to 2001, a total of 760 with a histologic diagnosis of DTC being managed at our institution were included to the present study. Of these, 734 (96.6%) patients were operated at our institution. The majority were female (80.5%) and ethnic Chinese (93.7%). The median age of the entire cohort was 43.0 years (range: 10.0–89.0 years). There were 589 (77.5%) patients with papillary thyroid carcinoma (PTC) and 171 (22.5%) with follicular thyroid carcinoma. All histological variants of PTC (n = 170, 22.4%) and FTC such as Hurthle cell carcinoma (n = 22, 2.9%) were included. The most common non-classical PTC variants were follicular (FVPTC) (n = 73, 9.6%), encapsulated (n = 31, 4.1%) and tall-cell (n = 23, 3.0%) variants. To ensure consistency and accuracy, each histologic diagnosis was reconfirmed after a careful review of the retrieved slides by a dedicated pathologist (KYL) who was unaware of the clinical data. All histologic diagnoses were made according to the standardized criteria approved by World Health Organization.15 Table 2Go summarizes the clinicopathological characteristics of the 760 patients with DTC.


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  		TABLE 2. Clinicopathological characteristics of 760 patients with differentiated thyroid carcinoma
 
Surgical Treatment and Adjuvant Therapy
For those patients with a preoperative diagnosis of DTC, a total or near-total thyroidectomy (which is defined as leaving less than 1 g of thyroid tissue behind) had increasingly been the preferred procedure of choice. For those diagnosed after a lobectomy, the decision whether to perform a completion total thyroidectomy and/or to administer radioiodine (RAI) ablation afterwards was determined by known risk factors such as the patient’s age, tumor characteristics as well as patient’s preference. If patients underwent completion total thyroidectomy within 6 months of their initial thyroid surgery, it was considered part of initial surgery. However, if re-operations were performed for residual or nodal disease 6 months after diagnosis, it was considered to be locoregional recurrence. Routine palpation and sampling of enlarged or suspicious lymph nodes in the central and lateral compartments was performed at the time of operation and was supplemented with the more frequent use of preoperative ultrasonography of the neck +/– fine needle aspiration cytology. A selective neck dissection, as defined as the clearance of cervical lymph nodes in levels II–V while preserving internal jugular vein and accessory nerve, was performed for cytologically or histologically proven lateral lymph node metastasis.

Patients with at least one or more of the following risk factors would be considered for RAI ablation 4–6 weeks after surgical treatment by T4 withdrawal: tumor size >1 cm, lymph node metastasis, age older than 40 years, presence of extrathyroidal extension, macroscopic postoperative residual disease in the neck, and/or distant metastasis. Diagnostic whole-body I131 scans were performed at 8–12 weeks after RAI therapy. Three gigabecquerels (GBq; 80 mCi) I131 would be administered as standard ablative dose while subsequent I131 therapy would be performed with 5.5 GBq (150 mCi). Additional 5.5 GBq I131 therapy would be administered periodically at 4–6 monthly intervals until uptake was no longer visible or disease progressed despite treatment. External local radiotherapy would be given to patients with extensive extrathyroidal tumor extension, incomplete resection and/or extra-capsular lymph node metastasis. Although the above protocol was strictly followed, individual patients’ preference would be considered and respected.

Follow-up and Surveillance of Patients
Complete medical records and follow-up data were available in all patients. The median follow-up period for the whole patients’ cohort was 118 months (range: 0.3–97.3). Patients with PTC was followed up over a median period of 93 months (range: 0.3–97.3) while those with FTC was 119 months (range: 0.5–488.3). All patients after surgery were followed up within 4 weeks in a specialized combined surgical oncology clinic where clinical oncologists and endocrine surgeons were present to discuss and decide on subsequent management. Follow-up visit was conducted at 3-monthly interval in the first 2 years, 6 monthly for the subsequent 3 years and annually thereafter. Clinical examinations, chest X-ray, ultrasonography of neck and thyroglobulin levels (since 1989) were done during follow-up visits. Human recombinant TSH was not available during the study period at our institution. Radioactive scans were done in the presence of elevated thyroglobulin level, documented nodal recurrence or radiological evidence of recurrence or metastases. The diagnosis of distant metastases on presentation was based on findings of histological, radiological or scintigraphic evidence and not based on an elevated thyroglobulin level only. Locoregional recurrences were frequently diagnosed by ultrasound, CT or MRI imaging and confirmed by fine needle aspiration cytology. Survival data including the cause of death were retrieved from the Hong Kong Hospital Authority territory-wide computerized medical system and from death certificates or postmortem examinations if available. The present study protocol was approved by the appropriate institutional review committee in accordance with the precepts established by the Helsinki Declaration.

Reclassification
All patients diagnosed with DTC before January 2005 were staged using the fifth edition TNM staging criteria.12 For the purpose of the present study and also as an update of our thyroid cancer database, all patients with thyroid cancer from 1956 to 2004 were retrospectively restaged or reclassified in accordance to the staging criteria in the sixth edition TNM.13 This reclassification process was done by a research nurse who was given time prior to this study to familiarize with the staging procedure in the AJCC cancer staging manual.14 She was unaware of the objectives of the present study. Both the operating record and the final histopathology report were reviewed and correlated in order to attain a separate pT and pN based on the sixth edition. This process was rechecked for discrepancies by BL. If no regional lymph nodes were found on the histopathology report, the pN was taken as N0.14 In case of discrepancies or uncertainties from the staging reclassification, either BL or CYL would decide after a review of all records.

Statistical Analysis
Survival was calculated from the date of initial surgery to the date of death or last follow-up. The end-point for the present analysis was cancer-specific survival (CSS). For each edition, CSS were calculated by the Kaplan–Meier method and were compared by the log-rank test. Using Cox proportional hazards analysis, the relative predictability of each edition was determined by calculating the proportion of variation in survival time explained (PVE). PVE (%) ranges from 0 to 100% with larger percentages suggesting better predictability. Therefore, the edition with the larger PVE would suggest a better predictor on CSS. To determine PVE, a mathematical formula was used: PVE = 1 – exp(–G2/n), where G2 is the maximum likelihood ratio that is determined by analysis of {chi}2 associated with the null hypothesis (i.e. that all predictor variables have coefficients of 0) and n is the total number of valid cases in the study.16 p < 0.05 was considered to indicate statistical significance. Statistical analyses were performed using the SPSS for Windows 11.0 computer software (SPSS Inc., Chicago, IL, USA).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
pT
The median tumor size was 2.5 cm (range: 0.1–14.0 cm). Based on the fifth edition, 108 (14.2%) patients with a tumor diameter ≤1 cm were classified as T1 whereas 336 (44.2%) patients with a tumor limited to the thyroid capsule and size >1 and ≤4 cm were classified as T2. The total number of T1 and T2 tumors remained at 444 (58.4%) in the fifth and sixth editions. However, based on the sixth edition, 146 (19.2%) cases were reclassified from T2 to T1. Therefore, there were 254 (33.4%) cases being reclassified as T1 and 190 (25.0%) cases as T2.

Similarly the total number of T3 and T4 remained at 316 (41.6%) in the fifth and sixth edition. Based on the sixth edition, 180 (23.7) patients were reclassified from T4 to T3, leaving 60 (7.9%) patients remained as T4. These 60 patients were further categorized into the T4a (n = 51 or 6.7%) and T4b (n = 9 or 1.2%). In summary, after reclassification, the number of T3 tumors was increased from 76 (10.0%) to 256 (33.7%) whereas the number of T4 tumors was decreased from 240 (31.6%) to 60 (7.9%).

pN
Based on the fifth edition, there were 501 (66.0%) patients with no metastasis to either the cervical or mediastinal lymph node (N0), 195 (25.7%) with metastasis to ipsilateral cervical lymph nodes (N1a) and 64 (8.4%) cases with metastasis to either bilateral, midline or contralateral cervical or mediastinal lymph nodes (N1b). Based on the sixth edition, there were 36 (4.7%) patients with metastasis to central and not to lateral compartment(s) (N1a). The number of N0 remained 501 (66.0%) and N1b increased from 64 (8.4%) to 223 (29.3%).

Tumor Stage Grouping
Table 3Go summarizes the changes in allocation of patients into different tumor stages as a result of the sixth edition tumor stage grouping reclassification. Based on the sixth edition, there were 458 (60.3%) patients assigned to stage I. A 35 (4.6%) patients were reclassified from stages II to I as result of the reclassification and an additional 15 (2.0%) patients were reclassified from stages II to III. As a result, only 106 (13.9%) patients remained in stage II. A 155 (20.4%) stage III patients were reclassified into stages IVA (n = 103, 13.6%) and IVB (n = 5, 0.7%) while only 47 (6.2%) patients remained in stage III. All of the stage IV patients were reassigned to stage IVC (n = 26, 3.4%). In summary, after reclassification to the sixth edition, there was an increase in stages I and IV patients from 423 (55.7%) to 458 (60.3%) and 26 (3.4%) to 134 (17.6%), respectively and there was a corresponding decrease of stages II and III patients from 156 (20.5%) to 106 (13.9%) and 155 (20.4%) to 62 (8.2%), respectively.


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  		TABLE 3. Allocation of patients into tumor stages as a result of the sixth edition TNM tumor grouping
 
Survival Outcome and Predictability
The CSS rate for the entire patient cohort at 5, 10 and 15 years were 94.7, 90.5 and 87.9%, respectively. A total of 129 deaths occurred up to the date of analysis, with 67 from DTC, 22 from other malignancy and 40 from concomitant medical illness. Confirmation of cause of death was supported by postmortem examination in 29 cases and the remaining cases were based on death certificate reports. In terms of tumor recurrences, 78 DTC patients developed recurrence but were rendered disease free after treatments with a median follow-up of 181 months (range: 72–419) whereas 27 were alive with recurrence with a median follow-up of 74 months (range: 69–113). A total of 121 and 36 patients had locoregional and distant recurrences, respectively. Twenty-three patients had both locoregional and distant recurrences.

Table 4Go summarizes the CSS and PVE value for the fifth and sixth editions of the TNM staging systems. Overall, both editions predicted CSS significantly (p < 0.001). Figure 1Go shows the CSS curve of 760 DTC by the fifth edition of TNM while Fig. 2Go shows the CSS curve of 760 DTC by the sixth edition of TNM. In terms of predictability as measured by PVE, the sixth edition had a higher PVE value (18.1% versus 16.3%) than the fifth edition. With the exception of stages IVB and IVC in the sixth edition, a higher tumor stage predicted a worse CSS. This apparent discrepancy could have resulted from the relatively small number of tumors and deaths in stage IVB. In terms of CSS distribution between tumor stages, the spread was more even in the fifth than in the sixth edition as p-values were highly significant between tumor stages in the fifth edition. In the sixth edition, the p-values between stages II and III and stages IVB and IVC were not significant (0.35 and 0.73, respectively).


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  		TABLE 4. Comparison of cancer-specific survival and predictability between tumor stages for the fifth edition and sixth edition of the AJCC/UICC TNM staging systems
 

Figure 1
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  		FIG. 1. Cancer specific survival of 760 differentiated thyroid carcinoma by the fifth edition TNM staging system.

 

Figure 2
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  		FIG. 2. Cancer specific survival of 760 differentiated thyroid carcinoma by the sixth edition TNM staging system.

 
Table 5Go shows a comparison of CSS between the fifth and sixth editions of TNM by tumor stage. There were no significant differences in stages I and II tumors (p = 0.767 and 0.582, respectively). However, there was a significant difference in stage III tumors (p = 0.013). Since there were only four stage groupings in the fifth edition, the CSS in stage IV was compared to the sixth edition stages IVA, IVB and IVC. The CSS in the fifth edition stage IV was significantly different from that of the sixth edition stage IVA (p = 0.021) tumors but not from that of stages IVB and IVC tumors (p = 0.726 and 1.0, respectively).


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  		TABLE 5. Comparison of cancer specific survival between the fifth and sixth editions of AJCC/UICC TNM staging system by tumor stage
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Cancer staging is an essential and integral part of cancer management. A predictive staging system not only provides clinicians and their patients with useful prognostic information relevant to the cancer itself but also helps to facilitate and standardize cancer information exchange between different medical centers for research purpose.17

The TNM system had been shown to be a highly predictive and widely accepted staging system for DTC18–20 when compared to other commonly used staging systems such as EORTC,2 AMES,3 NTCTCS,4 clinical class,21 MACIS22 and Ohio State University.23 However, unlike the other commonly used staging systems for DTC,2–4,21–23 it is regularly reviewed and revised by a panel of thyroid cancer experts.5 The purpose of this review process is to make the staging system compatible to the prevailing view on cancer staging and management.5 The current or the sixth edition TNM came into use since January 2003 and the next edition is expected to come out after 2008. To our knowledge, there have been so far three studies focusing on effects on outcome as a result of restaging from fifth to sixth edition but they were primarily concerned with the new pT on survival. The first study found that tumor size >1 cm was not associated with a worse outcome and so concluded that the sixth edition T1 criterion of 2 cm seemed appropriate.7 The second study was also concerned with the sixth edition T1 criterion and found that disease-free survival (DFS) appeared worse in the new T1 tumors than previous T1 tumors.8 The third study evaluated the effect of minimal extrathyroidal involvement (i.e. T3 based on the sixth edition TNM) on DFS.9 None of these studies actually evaluated the potential changes in CSS as a result of restaging of the same cohort within a single institution using the sixth edition TNM.

As a result of the sixth edition TNM reclassification, the proportion of T1 and T3 increased from 14.2 to 33.4% and 10 to 33.7%, respectively while the proportion of T2 and T4 decreased from 44.2 to 25.0% and 31.6 to 7.9%, respectively. Similar findings were observed in one previous study of 169 DTC patients but in that study, no patient had a T4 tumor probably due to the relative small number of DTC studied.8 In terms of the pN, there were significant changes noted. The proportion of N0 remained unchanged at 66.0% but the proportion of N1a decreased from 25.7 to 4.7% while N1b increased from 8.4 to 29.3%. However, these changes should be cautiously interpreted because routine central compartment sampling was not practiced during the study period, particularly for incidental microcarcinoma and low-risk tumors. Since the incidence of lymph node metastases had been reported as high as 60–70%,24,25 our incidence of central lymph node metastases might have been underestimated.

Tumor stage grouping is a unique and important feature of the TNM because it allows for more convenient usage of the staging system by condensing the T, N and M categories into convenient number of stage groups.26 The number of stage groupings was increased from four to six after the sixth edition came into use. As a direct consequence of the sixth edition stage grouping, the proportion of stages I and IV tumors increased from 55.7 to 60.3% and 3.4 to 17.6%, respectively, while the proportion of stages II and III tumors decreased from 20.5 to 13.9% and 20.4 to 8.2%, respectively. Similar changes in tumor stages were observed in one previous study of 299 patients.7 However, these were not shown in another similar study where the proportion of stage III tumors was found to have increased from 27 to 33% while the proportion of stage IV tumor remained at 3.0%.8

Both the fifth and sixth editions TNM significantly predicted the CSS of our cohort (p < 0.001). When predictability for CSS within each edition was measured by PVE, the sixth edition had a higher PVE value than the fifth edition TNM (18.1% versus 16.3%). This meant that overall the sixth edition may be a better predictor of CSS than the fifth edition but this should be interpreted cautiously as the number of tumors and deaths were small in stage IVB and that could have led to a falsely low CSS and so a slightly better overall PVE value because of a broader range of CSS among all stages. Our finding did concur with that of a previous study of 299 patients that the sixth edition appear to perform better than the fifth edition but in that analysis, only tumors with size smaller than 1.5 cm were included. Further studies with larger sample size would be required to confirm our finding.

Interestingly though, when CSS were compared between tumor stages within each edition, our results showed that based on the sixth edition, stages II and III as well as stages IVB and IVC did not demonstrate significant differences in CSS. In other words, the sixth edition stages II and III tumors had similar predictive CSS and the same applied to stages IVB and IVC tumors. As aforementioned, since routine central lymph node sampling was not performed, some of the stage III tumors might have been understaged as stage II tumors. For example, patients aged ≥45 years with a T2 N1a M0 tumor would have been staged as a T2 Nx M0 or stage II tumor. Another alternative explanation might have been that the number of patients and deaths in these stages were simply insufficient to demonstrate a significant difference in CSS but to our knowledge, the present study is the largest of its kind and this similar problem was observed in the other three studies.7–9 Nevertheless, our results did suggest that the spread of CSS appeared less evenly distributed in the sixth edition TNM. Further studies would be required to determine whether these tumor stages with similar CSS should be grouped together for convenience in the future.

To determine whether there were any changes in CSS within each tumor stage as a result of reclassification, the CSS within each tumor stage were compared between the two editions. There were significant differences in CSS between stage III (fifth edition) and stage III (sixth edition) and between stage IV (fifth edition) and stage IVA (sixth editions). Since any significant differences in CSS within a tumor stage would be a result of the differences in tumor group staging and staging method rather than the actual differences in the physical extent of disease, these could be interpreted as a stage migration phenomenon.1 The present study attempted to standardize the reclassification process by having the same person who was blinded to patients’ fifth edition tumor stages to recode all 760 DTC patients. The instructions in the AJCC cancer staging manual (2002) were also closely adhered to in this study and the final tumor stages were rechecked by another person. Therefore, the authors believed that the significant differences in CSS were a direct result of the changes in the sixth edition TNM staging method and not a result of inaccurate restaging. Both stages III and IVA tumors in the sixth edition had significantly better CSS than their equivalent counterparts in the fifth edition. Clinicians should be aware of these differences and should not assume that equivalent tumor stages in the two editions TNM have similar CSS. Such situation may occur when the prognosis of one group of DTC is compared with that of a historical control group based on tumor stages and both groups are staged by different editions of TNM.

The issue of whether the stage specific treatment should now be modified as a result of subtle differences in CSS within each tumor stage after reclassification remains unclear as treatment protocols vary slightly among different institutions.10 In our institution, at least, the treatment strategy would not change significantly as a result of this reclassification from the fifth to sixth edition TNM because those with either the fifth or the sixth TNM stage I tumors would still be regarded as the low-risk group whereas those with more advanced or higher staged tumors, a total thyroidectomy followed by RAI would be recommended as a standard treatment. However, based our findings under the sixth edition TNM, the recommended protocol for surgical and adjuvant treatment should remain similar for stages II and III as well as for stages IVB and IVC tumors.


   CONCLUSIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Upon reclassification to the current or sixth edition of TNM, marked changes were noted in the pT and pN. In addition, the sixth edition tumor stage grouping resulted in marked changes in the allocation of patients into tumor stages. Both editions predicted CSS significantly (p < 0.001). When PVE was used as a method of evaluating predictability for CSS, the sixth edition TNM appeared to be superior to the fifth edition. Significant differences in CSS were observed between stage III (fifth edition) and stage III (sixth edition) and between stage IV (fifth edition) and stage IVA (sixth edition).

Received for publication May 29, 2006. Accepted for publication August 21, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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